Introduction: The Persistent Challenge of Drug-Resistant Focal Epilepsy
Historically, the management of drug-resistant focal epilepsy (DRFE) has been a process of trial and error. Despite the introduction of numerous third-generation antiseizure medications (ASMs) over the last two decades, approximately one-third of patients continue to experience seizures despite appropriate trials of two or more tolerated and appropriately chosen ASM regimens. The definition of drug resistance, established by the International League Against Epilepsy (ILAE), underscores a significant unmet medical need: achieving seizure freedom remains the ultimate clinical goal, yet it is elusive for many.
The Shift Toward Comparative Effectiveness
While randomized clinical trials (RCTs) are the gold standard for drug approval, they often utilize highly selected populations and short follow-up periods that do not fully reflect the complexities of clinical practice. In the absence of head-to-head RCTs, clinicians have long sought comparative effectiveness data to guide the selection of adjunctive therapies. The Comparative REal-World Evidence (CREW) study addresses this gap by comparing four common third-generation ASMs: brivaracetam, cenobamate, lacosamide, and perampanel.
Study Design and Methodology
The CREW study was a multicenter, retrospective, real-world medical record-review study conducted across 71 epilepsy centers. The analysis pooled data from four previously conducted studies between January 2017 and January 2024, focusing on adult patients (aged 16 years or older) with a confirmed diagnosis of drug-resistant focal epilepsy.
Participant Demographics and Exposure
The analysis included 1,993 prescriptions from 1,949 patients. The median age of the cohort was 42 years, and 53.2% of the participants were female. The distribution of ASM prescriptions was as follows: brivaracetam (47.8%), perampanel (30.5%), lacosamide (12.1%), and cenobamate (9.6%). Patients were treated with these medications as add-on (adjunctive) therapies to their existing regimens.
Outcome Measures
The primary outcome was the 50% responder rate at 6 months, defined as a reduction in seizure frequency of 50% or more from the baseline. Secondary outcomes included the 12-month responder rate, seizure freedom (defined as at least 3 months of no seizures at the 6-month mark and at least 6 months at the 12-month mark), and 12-month treatment retention. Safety was evaluated through the incidence of adverse effects (AEs). Researchers used generalized linear mixed models to adjust for demographic and clinical variables, using cenobamate as the reference drug.
Key Findings: Cenobamate as a Potential Game-Changer
The results of the CREW study provide compelling evidence for the superior effectiveness of cenobamate in this difficult-to-treat population.
Superior Responder Rates
At the 6-month mark, cenobamate demonstrated significantly higher odds of achieving a 50% or greater response compared to all three other medications. Specifically, brivaracetam showed an odds ratio (OR) of 0.18 (95% CI, 0.12-0.28), perampanel an OR of 0.26 (95% CI, 0.16-0.42), and lacosamide an OR of 0.29 (95% CI, 0.17-0.49). These statistics indicate that cenobamate was associated with a much higher likelihood of substantial seizure reduction.
Long-Term Effectiveness and Seizure Freedom
The effectiveness of cenobamate was maintained at 12 months. Cenobamate outperformed the other ASMs in both 12-month responder rates and, perhaps most importantly, in seizure freedom rates. In the context of drug-resistant epilepsy, where seizure freedom is often considered a distant hope, these findings suggest that cenobamate may offer a higher ceiling for therapeutic success.
Retention and Tolerability
Treatment retention—a composite measure of both effectiveness and tolerability—also favored cenobamate. At 12 months, cenobamate was associated with a higher likelihood of retention compared with brivaracetam (OR, 0.43) and perampanel (OR, 0.56). Interestingly, there was no significant difference in retention when compared to lacosamide (OR, 0.81), suggesting that while patients might experience more side effects with cenobamate, the clinical benefit often justifies continuing the medication.
Safety Profile: The Trade-off of Potency
The study did not ignore the safety aspect of these potent medications. Cenobamate was associated with the highest rate of adverse effects during follow-up, reported in 57.8% of prescriptions. In contrast, lacosamide was associated with the lowest rate of adverse effects at 14.8%. The higher incidence of AEs with cenobamate—which can include somnolence, dizziness, and fatigue—highlights the need for careful titration and patient monitoring. However, the high retention rate suggests that these AEs are often manageable or that the reduction in seizure burden outweighs the burden of side effects for many patients.
Mechanistic Insights: Why Cenobamate Differs
The superior effectiveness observed in the CREW study may be linked to cenobamate’s unique dual mechanism of action. Unlike lacosamide and brivaracetam, which primarily target voltage-gated sodium channels (specifically the inactivated state) or the synaptic vesicle protein 2A (SV2A), respectively, cenobamate acts as both a positive allosteric modulator of the GABA-A receptor at a non-benzodiazepine site and a potent inhibitor of the persistent component of the sodium current. This multifaceted approach to modulating neuronal excitability may explain its enhanced ability to suppress focal seizures that have failed to respond to more single-targeted agents.
Expert Commentary and Clinical Implications
From a clinical perspective, the CREW study provides a robust justification for the earlier consideration of cenobamate in the treatment algorithm for focal epilepsy. For years, the choice of a third-generation ASM was largely guided by the side-effect profile or ease of titration. These data suggest that when the priority is achieving significant seizure reduction or seizure freedom, cenobamate may be the preferred choice despite its more complex titration schedule and higher AE profile.
Limitations and Considerations
As with any retrospective real-world study, there are limitations. The choice of ASM was at the discretion of the treating physician, which can introduce prescription bias. Additionally, while the study adjusted for many covariates, unmeasured factors such as specific genetic markers or detailed previous treatment histories could influence the results. The smaller sample size for the cenobamate group compared to brivaracetam also reflects its more recent entry into many markets during the study period.
Conclusion
The findings from the CREW study mark a significant step forward in the evidence-based management of drug-resistant focal epilepsy. By demonstrating the superior effectiveness of cenobamate over brivaracetam, lacosamide, and perampanel in a large-scale real-world setting, the study provides clinicians with the data needed to make more informed decisions. While the management of side effects remains a priority, the potential for achieving seizure freedom with cenobamate offers a significant advancement for patients who have long struggled with uncontrolled epilepsy.
References
Cerulli Irelli E, Roberti R, Borioni MS, et al. Comparative Effectiveness of Brivaracetam, Cenobamate, Lacosamide, and Perampanel in Focal Epilepsy. JAMA Neurol. Published online February 9, 2026. doi:10.1001/jamaneurol.2025.5625.
